Sniffing Out Hedgehog in Tumors

An embryo and a tumor share a key feature: rapid cell division. For years, scientists have probed this connection. Now, two independent teams of researchers have found that in certain tumors, a set of genes critical to normal development, called the Hedgehog pathway, is overactive and spurs tumor growth. The finding could eventually guide drug development for cancers that lack effective treatment.

The Hedgehog pathway ensures that an embryo's body is properly organized. Hints that it's also involved in cancer surfaced in the 1990s, when researchers found that it was overactive in Gorlin's syndrome, a rare condition that predisposes sufferers to various cancers. More recently, Philip Beachy, a molecular and developmental biologist at Johns Hopkins University in Baltimore, Maryland, and his colleagues determined that inhibiting the pathway blunts growth of childhood brain tumors and some types of lung cancer. Now, Beachy and his colleagues, as well as a group in Boston and San Francisco, have turned to another class of tumor: those affecting the digestive tract. They already knew that the Hedgehog pathway helps much of the digestive tract develop.

To see whether it drives cancer, Beachy's team analyzed tumors from the esophagus, stomach, biliary tract, pancreas, and colon. In the first four, Hedgehog and other key pathway genes were often anywhere from 20 to 5000 times more active than normal. The exception was the colon, which doesn't appear to be guided by Hedgehog in embryonic development. Next, Beachy and his colleagues injected cancer cells from tumors with overactive Hedgehog into mice without a functioning immune system, and the mice developed tumors. Then they added a drug called cyclopamine, which inhibits the Hedgehog pathway; it made the tumors disappear, implicating Hedgehog even more directly.

A second group, led by cancer surgeon Sarah Thayer at Massachusetts General Hospital in Boston and developmental biologist Matthias Hebrok at the University of California, San Francisco, focused on pancreatic tumors, an invariably fatal cancer. They found that the Hedgehog pathway was overactive in all 26 human cancer cell lines they screened; but cyclopamine destroyed only about half of the dozen lines tested. This could mean that not all pancreatic tumors require Hedgehog activity for survival. Both papers appear online this week in Nature.

"It's potentially extremely significant," says Steven Leach of Johns Hopkins University, who studies links between pancreatic development and pancreatic cancer. "It sparks hope that if we can manipulate these pathways ... it may facilitate chemoprevention or early detection"--although he cautions that that possibility is years from fruition.